Vertebral fractures are the most common osteoporotic fracture, occurring in 1/3 of women and 1/6 of men over age 50. They cause significant morbidity and increased mortality, and are among the strongest risk factors for future fractures. Despite the high and growing occurrence, personal and societal costs, the biomechanical mechanisms that underlie vertebral fractures remain obscure, in particular why they occur preferentially at the mid-thoracic and thoraco-lumbar regions of the spine. Recently, we showed that the ratio of skeletal loading to bone strength explains much of the age- and sex-specific patterns of fractures. Thus, we propose that a better understanding of the mechanisms underlying vertebral fracture can be gained by a biomechanical approach that relates the loads applied to the spine to vertebral strength at specific regions along the spine. Our overall hypothesis is that the age-, sex- and location-specific patterns of vertebral fracture can be explained by assessing the ratio between vertebral strength and spinal loading. To address this, we propose two specific aims. In Aim 1 we will use age- and sex-stratified sample of 872 previously acquired 3D quantitative computed tomography (QCT) scans of the thoracic and lumbar spine from 3529, men and women (aged 31 - 83), enrolled in the "Framingham Heart Study Offspring and Third Generation Multidetector CT Study" to compare the ratio of spine load to vertebral strength (i.e., the factor-of-risk), in men and women, across the lifespan, and along the spine. In Aim 2 we will use the cohort from Aim 1 to conduct a case-control study comparing the factor-qf-risk m without prevalent vertebral fractures. Also, we will'compare vertebral'Strength estimates from .two JQCT-! based methods:'yoxelrbased ^finite .ejem^ent, a^ study will provide novel information about vertebral fractures, because despite the high occurrence of fractures in the thoracic spine, no population-based studies have assessed age- and sex-related variation in vertebral strength and/or spine loading in the thoracic region. In summary, by drawing on state-of-the-art 3D quantitative computed tomography (QCT) scans and high quality clinical data already obtained within a sub-study of the well-characterized Framingham Heart Study cohorts, the proposed project will be innovative and highly cost effective. This population-based study will provide new insights into the pathophysiology of vertebral fractures by employing a biomechanical approach to fracture risk assessment, and by studying, for the first time, bone density and geometry and trunk muscle morphology in both the thoracic and lumbar spine in men and women over a wide age range. The findings will have important public health implications, as a better understanding of the interaction between bone density, geometry and spinal loading may lead to improved diagnosis of individuals at risk for fracture and to targeted therapeutic interventions for prevention and treatment of vertebral fractures. [unreadable] [unreadable] [unreadable] [unreadable]